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Sildenafil Improves Clinical Signs and Radiographic Features in Dogs With Paper Paper Sildenafil improves clinical signs and radiographic features in dogs with congenital idiopathic megaoesophagus: a randomised controlled trial F. Quintavalla, A. Menozzi, C. Pozzoli, E. Poli, P. Donati, D. K. Wyler, P. Serventi, S. Bertini We evaluated the efficacy of oral sildenafil citrate in dogs with congenital idiopathic megaoesophagus (CIM). Twenty-one puppies were randomly assigned to two groups (treatment and control). The dogs were given sildenafil oral suspension 1 mg/kg every 12 hours for 14 days or placebo in a masked fashion. Clinical signs (frequency of regurgitation and weight gain) and oesophagrams (relative oesophageal diameter, ROD) were evaluated in order to assess the efficacy of drug treatment, by examiners who were unaware of the study protocol. In addition, a set of in vitro experiments on isolated samples of canine lower oesophageal sphincter (LOS) was performed, and the effects of increasing concentrations of sildenafil on basal tone and electrically-stimulated motility were assessed. Sildenafil administration significantly reduced the number of regurgitation episodes (0.88 ±1.40 v 2.65±1.56, P<0.0001) and significantly increased weight gain in the treated dogs compared to controls (79.76±28.30 per cent v 53.40±19.30 per cent, P=0.034). ROD values, at the end of the treatment period, were significantly decreased in the sildenafil group, compared to pre-treatment values (0.97±0.19 v 0.24±0.14, P<0.0001), in contrast to control subjects (0.98±0.17 v 1.10±0.25, P=0.480). In accordance with the in vivo findings, sildenafil dose-dependently reduced basal tone and increased electrically-induced relaxation of dog LOS samples. These results suggest that sildenafil citrate helps ameliorate clinical and radiographic signs in dogs with CIM by reducing LOS tone, and could represent a novel therapeutic tool for the treatment of this disease. Introduction frequently affects more than one animal in the same litter The term megaoesophagus is used to describe a disease charac- (Harvey and others 1974, Glidewell 1983). terised by reduced or absent oesophageal motility which causes the CIM causes poor weight gain (WG) in puppies shortly after accumulation of ingesta, dilatation of the oesophageal lumen, food weaning, and, even though most animals tend to show spontan- regurgitation (which is often mistaken for vomit by the dog eous improvement over time, they require long-lasting physical owner), and weight loss as the main clinical signs. Megaoesophagus and nutritional support, and the risk of fatal complications such may be idiopathic, congenital or acquired, or secondary to differ- as aspiration pneumonia is high. ent aetiologies, such as myasthenia gravis, hypothyroidism or The pathogenesis of CIM is currently unclear. A predispos- Addison’s disease. Congenital idiopathic megaoesophagus (CIM) ition for the disease has been reported in large and giant-breed is often observed at or before 10 weeks of life, and the condition dogs such as the German shepherd, Great Dane, Irish setter, Labrador retriever, Irish wolfhound and Newfoundland (Knowles and others 1990), and genetics might play a role in the Veterinary Record (2017) doi: 10.1136/vr.103832 aetiology of CIM because autosomal dominant inheritance has been demonstrated in miniature Schnauzers and fox terriers F. Quintavalla, DVM, Cerro Maggiore, Milano, Italy (Washabau 2003). A suspected hereditary form has also been A. Menozzi, DVM, PhD, D. K. Wyler, DVM, reported in Bouvier des Flandres dogs (Peeters and others 1991). P. S e r v e n t i , BSc, The Animal Medical Hospital and It has been hypothesised that the congenital form of the S. Bertini, DVM, PhD, Whitestone Veterinary Care, New York, disease is linked to a reduced or delayed development of the Department of Veterinary Science, NY, USA oesophageal neuromuscular system, in particular of the afferent University of Parma, Parma, Italy E-mail for correspondence: alessandro. vagal innervation, which fails to respond to the mechanical C. Pozzoli, PhD, [email protected] stimulus induced by food, thus resulting in ineffective peristalsis E. Poli, PhD, (Holland and others 1994, 1996, 2002). Manometric studies have Department of Neuroscience, Provenance: Not commissioned; found a normal tone and functioning of the lower oesophageal University of Parma, Parma, Italy externally peer reviewed sphincter (LOS) in dogs with idiopathic megaoesophagus P. D o n a t i , DVM, Accepted January 23, 2017 (Diamant and others 1973), unlike in other oesophageal motility 10.1136/vr.103832 | Veterinary Record | 1of6 Paper disorders in humans, such as achalasia or diffuse oesophageal beginning of the study, and none had been previously treated spasm, where a hypertonicity of sphincter muscle is present with prokinetic drugs. (Pohl and Tutuian 2007, Roman and Kahrilas 2012). However, a The present study was conducted as a randomised controlled failure by the LOS to relax in response to intraluminal balloon trial; therefore the dogs eligible for enrolment were randomly distension has been observed (Tan and Diamant 1987), further assigned to two parallel groups, treatment and control (placebo), supporting the hypothesis of a functional defect of oesophageal with an allocation ratio of 1:1. sensory innervation. Informed consent about the nature of the diagnostic and CIM treatment is frustrating, resulting in high mortality experimental procedures to be performed was obtained from the from directly related causes such as malnutrition and aspiration dog owners (breeders), before enrolling their puppies. The trial pneumonia or because euthanasia is required due to the continu- was conducted in compliance with institutional guidelines for ing clinical signs (Harvey and others 1974, McBrearty and others research on animals, and it was approved by the Ethics 2011). In the majority of cases, drugs are not adequately effect- Committee of the University of Parma (O.P.B.A.), Prot. N. 136/ ive, and the treatment is based mostly on nutritional support OPBA/2016. and alterations in body position (Chandra and others 1989). Each dog was given the daily amount of food, according to Several pharmacological approaches, especially with prokinetic the caloric requirements of each breed, divided into six equal drugs such as metoclopramide, domperidone or cisapride, have small meals. All the dogs were fed with the same homogenised been proposed, with modest or varying results (Washabau 2003). commercial canned puppy food from an elevated position, and However, recent studies with high-resolution manometry none was managed with a percutaneous endoscopy gastrostomy showed that cisapride significantly increased LOS pressure in tube. Moreover, all the dogs were kept in an elevated position for healthy dogs, and this could represent a serious concern in dogs 10 minutes after each meal, and carefully observed for the fol- with megaoesophagus (Kempf and others 2014, Ullal and others lowing 30 minutes to detect possible regurgitation episodes. For 2016). each dog, the breeder was asked to randomly choose one of two Swallowing and oesophageal motility are complex processes identical bottles (labelled ‘A’ and ‘B’), and therefore was masked involving a multifaceted interplay between excitatory innerv- to the nature of the content. Bottles labelled ‘A’ contained silde- ation, mostly vagal cholinergic fibres, and inhibitory innervation, nafil citrate (Revatio 10 mg/ml oral suspension, Pfizer Italia), which releases nitric oxide (NO) as the main neurotransmitter. whereas the bottles labelled ‘B’ contained placebo, that is, a sus- Endogenous NO induces smooth muscle relaxation through the pension prepared with only water and the excipients present in synthesis of the second messenger cyclic guanosine monopho- Revatio commercial formulation, and with the same physical sphate (cGMP). Sildenafil, a selective phosphodiesterase-type 5 aspect. A dose of 0.1 ml/kg of suspension ‘A’ or ‘B’ was adminis- (PDE-5) inhibitor, indirectly potentiates the action of endogen- tered directly into the oral cavity of each dog, using a syringe, ous NO by reducing cGMP degradation due to PDE-5 (Zhu and every 12 hours for two weeks, by a member of our research others 2007). Sildenafil is an effective vasodilator and is widely group who was unaware of the treatment protocol. The dogs prescribed for the treatment of erectile disorders in man; allocated in the treatment group therefore received 1 mg/kg sil- however, it is also used to treat pulmonary hypertension, and it denafil every 12 hours; this dose was chosen on the basis of pre- relaxes the smooth muscle of other organs such as the uterus vious studies in humans and cats (Bortolotti and others 2000, (Méhats and others 2006) and the gallbladder (Degirmenci and Zhang and others 2004), in which the same dose was effective in others 2006). The vasorelaxant properties of sildenafil have also relaxing the LOS. In order to obtain a prolonged effect on LOS been observed in dogs (Souza-Silva and others 2005, Bach and tone, the drug was administered twice daily, since the half-life of others 2006), and this drug represents a valid option for the sildenafil in dogs is about five hours (Walker and others 1999). treatment of pulmonary hypertension in this species. The dogs’ owners were asked to record (on an appropriate In humans and cats sildenafil has already been shown to data sheet) the frequency of regurgitation occurring within a induce the relaxation of the LOS (Zhang and others 2001, Fox 24 hour period at different times: D0 (the day before the begin- and others 2007). Therefore, in the current study we evaluated ning of the treatment), D1 (first day of treatment), D2 (second the therapeutic efficacy of sildenafil in dogs affected by CIM, on day of treatment), D3 (third day of treatment), D4 (fourth day the premise that a decreased LOS tone would facilitate the entry of treatment), D5 (fifth day of treatment), D7 (seventh day of of the ingesta into the stomach, thus reducing the pressure treatment), D10 (10th day of treatment), D14 (14th day of treat- inside the oesophageal lumen.
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